Page 112 - Haematologica May 2020

M.N. Peiris et al.
Through this work, we have described potential approaches to inhibit BCR-FGFR1 induced SCLL. Although TKI therapies have been used to traditionally treat certain hematopoietic cancers, their use has often resulted in drug resistance. Recently it has been discovered that FGFR1 fusion kinases are associated with the upregu- lation of MYC, which drives SCLL.35 Targeting the MYC complex in addition to chemotherapy, and the approaches described here may also be therapeutically beneficial for patients with SCLL.
Relevance for BCR-ABL driven cancers
Since the initial characterization of BCR-ABL, the emer-
gence of cancer genome sequencing has played a vital role in the detection of other translocation-induced malig- nances. BCR-ABL is detected in 95% of CML cases, and variants of this gene exist with alternative breakpoints. The most commonly found transcript is the BCR-ABL p210 variant which contains a breakpoint of BCR exon 13 fused to exon 1 of ABL.10 In comparison to BCR-FGFR1, BCR-ABL retains more of the BCR gene in this fusion. However, both fusions retain the oligomerization domain, putative serine threonine/kinase domain and GEF domain. Due to the similarity between these fusions, we propose that the work described here will be relevant to BCR-ABL fusions as well. In particular, the inhibition of the BCR coiled-coil domain through salt bridge disruption may be an additional therapeutic target for BCR-ABL. Furthermore, retention of the GEF domain in BCR-FGFR1 has been shown to result in reduced leukemogenesis.36
Although TKI are usually the first line of treatment for CML, many patients will require concurrent forms of ther-
apy to ensure complete remission.37 Hsp90 inhibition has become an attractive therapeutic target in treating BCR-ABL induced CML. More recently, aminoxyrone was shown to be effective in inhibiting imatinib resistant CML.37 While Ganetespib binds to the N-terminal ATP binding site in Hsp90, Aminoxyrone binds to the C-termi- nal tail of Hsp90, preventing its dimerization. The combi- nation of Hsp90 inhibition with traditional chemotherapy and TKI treatment may be beneficial in patients with CML or SCLL. These recent findings again highlight the importance of the characterization of oncogenic transloca- tions as well as the development of additional therapeutic targets to treat therapy-refractory leukemia.
Acknowledgements
We thank all current lab members particularly Juyeon Ko, Fangda Li, and Clark Wang for advice and encouragement, Leo Gallo and Dan Crocker for additional support, and Alexandre R. Campos from Sanford Burnham Prebys (SBP) Medical Discovery Institute for analysis of samples by mass spectrometry. MNP gratefully acknowledges support from a UC San Diego San Diego Fellowship, and DJD gratefully acknowledges gener- ous philanthropic support from the UC San Diego Foundation. Support to the SBP Proteomics Facility from grant P30 CA030199 from the National Institutes of Health is also grate- fully acknowledged.
Dedication
MNP dedicates this work in memory of her parents Swarnakanthie Peiris (1947-2005) and Donald Peiris (1949- 2018), as this work would not have been possible without their inspiration, love and support.
References
1. Gallo LH, Nelson KN, Meyer AN, Donoghue DJ. Functions of Fibroblast Growth Factor Receptors in cancer defined by novel translocations and mutations. Cytokine Growth Factor Rev. 2015;26(4):425-449.
2. Macdonald D, Reiter A, Cross NC. The 8p11 myeloproliferative syndrome: a dis- tinct clinical entity caused by constitutive activation of FGFR1. Acta Haematol. 2002;107(2):101-107.
3. Nelson KN, Peiris MN, Meyer AN, et al. Receptor tyrosine kinases: translocation partners in hematopoietic disorders. Trends Mol Med. 2017;23(1):59-79.
4. Khodadoust MS, Luo B, Medeiros BC, et al. Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia. 2016;30(4):947- 950.
5. Verstovsek S, Rambaldi A, Asatiani E, et al. Phase 2, open-label, multicenter study to evaluate the efficacy and safety of INCB054828 in patients with myeloid/lym- phoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) rearrangement. Cancer Res. 2017;77(13 Suppl):Abstract nr CT057.
6. Cuesta-Dominguez A, Ortega M, Ormazabal C, et al. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCR-JAK2 tyrosine-kinase. PLoS One. 2012;7(2):e32451.
7. Ballerini P, Struski S, Cresson C, et al. RET fusion genes are associated with chronic myelomonocytic leukemia and enhance monocytic differentiation. Leukemia. 2012;26(11):2384-2389.
8. Baxter EJ, Hochhaus A, Bolufer P, et al. The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Hum Mol Genet. 2002;11(12):1391-1397.
9. Peiris MN, Li F, Donoghue DJ. BCR: a promiscuous fusion partner in hematopoiet- ic disorders. Oncotarget. 2019;10(28):2738- 2754.
15. Nelson KN, Meyer AN, Wang CG, Donoghue DJ. Oncogenic driver FGFR3- TACC3 is dependent on membrane traffick- ing and ERK signaling. Oncotarget. 2018;9(76):34306-34319.
16. Nelson KN, Meyer AN, Siari A, et al. Oncogenic gene fusion FGFR3-TACC3 is regulated by tyrosine phosphorylation. Mol Cancer Res. 2016;14(5):458-469.
17. Mulcahy LS, Smith MR, Stacey DW. Requirement for ras proto-oncogene func- tion during serum-stimulated growth of NIH 3T3 cells. Nature. 1985;313(5999):241-
10. Laurent E, Talpaz M, Kantarjian H, Kurzrock 243.
R. The BCR gene and philadelphia chromo- some-positive leukemogenesis. Cancer Res. 2001;61(6):2343-2355.
11. Hart KC, Robertson SC, Kanemitsu MY, et al. Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene. 2000;19(29):3309-3320.
12. Hu Y, Fang X, Dunham SM, et al. 90-kDa ribosomal S6 kinase is a direct target for the nuclear fibroblast growth factor receptor 1 (FGFR1): role in FGFR1 signaling. J Biol Chem. 2004;279(28):29325-29335.
13. Gallo LH, Meyer AN, Motamedchaboki K, et al. Novel Lys63-linked ubiquitination of IKKbeta induces STAT3 signaling. Cell Cycle. 2014;13(24):3964-3976.
14. Meyer AN, McAndrew CW, Donoghue DJ. Nordihydroguaiaretic acid inhibits an acti- vated fibroblast growth factor receptor 3 mutant and blocks downstream signaling in multiple myeloma cells. Cancer Res. 2008;68(18):7362-7370.
18. Daley GQ, Baltimore D. Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. Proc Natl Acad Sci U S A. 1988;85(23):9312-9316.
19. Ma G, Lu D, Wu Y, et al. Bcr phosphorylated on tyrosine 177 binds Grb2. Oncogene. 1997;14(19):2367-2372.
20. Roumiantsev S, Krause DS, Neumann CA, et al. Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198- FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations. Cancer Cell. 2004;5(3):287-298.
21. McWhirter JR, Galasso DL, Wang JY. A coiled-coil oligomerization domain of Bcr is essential for the transforming function of Bcr-Abl oncoproteins. Mol Cell Biol. 1993;13(12):7587-7595.
22. Cetinbas N, Huang-Hobbs H, Tognon C, et al. Mutation of the salt bridge-forming residues in the ETV6-SAM domain interface
1272
haematologica | 2020; 105(5)